Nowadays, corticoids or various non-steroidal anti-inflammatory agents are clinically widely used for the purpose of preventing complications due to inflammation. However, since although corticoids exhibit a strong anti-inflammatory action, grave side effects such as induction of infectious diseases accompany the action, they cannot serially be administered, and non-steroidal anti-inflammatory agents have only weak efficacy in general. Therefore, it is still needed to develop anti-inflammatory agents exhibiting almost no side effect and yet having sufficient efficacy.
Incidentally, in the screening systems by which anti-inflammatory agents as mentioned above had been developed, anti-prostaglandin actions (e.g., phospholipase A2 inhibition, cyclooxygenase inhibition, lipoxygenase inhibition) had generally been used as a measure. On the other hand, in this invention, the present inventors intend to solve the above problems from the viewpoint that an utterly novel-type of anti-inflammatory agents may probably be developed by utilizing a screening system constructed based on the findings on induction of inflammation being clarified recently (i.e., a screening system using as a measure inhibition of influx of neutrophils, more specifically, selectin-mediated inhibition of adhesion of neutrophils to vascular endothelial cells).
In order to clarify the sense of the screening system used in the invention, the findings of its background are outlined below. For example, inflammation is speculated to be induced by molecules promoting adhesive interactions between leukocytes and vascular endothelial cells, and it has also come to be clarified that certain adhesion promoting molecules play an important role for promotion of the adhesive interaction. Further, it is also revealed that adhesion promoting molecules exist in both leukocytes and activated vascular endothelial cells (blood vessel at the inflammation site), and interactions between these adhesion promoting molecules are the first indispensable stage for influx of leukocytes to the inflammatory site. These adhesion promoting molecules are molecules found in both leukocytes and activated vascular endothelial cells, and selectin family and integrin family are the most important as the molecules.
On the other hand, it is also reported to use, for control of the above interactions, monoclonal antibodies (Eur. J. Immunol., 23, 2181-2188, 1993), peptides and further certain oligosaccharides (J. Cell Biol., 99, 1535, 1984; Tednok et al., J. Cell Biol., 104, 713, 1987; Blood, 70, 1842, 1987). Further, although leukocytes adhere to endothelial cells in the lymph node through the above action of selectin, it is clarified that this response is inhibited by certain sulfate radical-containing compounds (J. Cell Biol., 111, 1225, 1990). It is still further reported that inflammatory response can be inhibited in various laboratory animal model by inhibiting the above adhesive interactions (J. Immunol., 150, 2407; J. Immunol., 150, 1074 etc.).
However, it is not clarified whether or not these monoclonal antibodies, peptides, oligosaccharides and sulfate radical-containing compounds can actually be used as anti-inflammatory agents.
The present inventors found that the neutrophil-dependent, oxygen radical-mediated and P-, L- or E- selectin-dependent inflammation model obtained by intravenous administration to rats of cobra venom factor (hereafter, sometimes abbreviated as "CVF"), recently proposed in M. S. Mulligan et al., Nature, 364, 149-151, 1993, is an excellent screening method for anti-inflammatory agents. More specifically, they found that specific polysaccharides such as sulfated hyaluronic acid screened using the above laboratory animal model exhibit excellent anti-inflammatory actions, and can, particularly, be used for prophylaxis or treatment of adult respiratory distress syndrome (ARDS). This syndrome is such a grave disease that 50 to 70% of patients suffering therefrom die (Igaku no Ayumi, 168 (no. 6), 626-631). It was further found that since substances screened using the above laboratory animal model inhibit the influx of neutrophils to the vascular endothelial adhesion tissue mediated by selectin, these substances show efficacy not only on ARDS but widely on general inflammations, and show efficacy further on ischemic heart diseases, ischemic cerebral diseases, chronic articular rheumatism, atopic dermatitis and infiltration after organ implantation.
In this connection, although it is suggested that sulfates of various saccharides including sulfated hyaluronic acid is usable for treatment of diseases caused by human immunodeficiency viruses (Japanese Patent Publication No. 7577/1990), it has not hitherto been disclosed in technical literatures that these saccharides can be used as anti-inflammatory agents.